The present invention relates to novel compounds which are protein kinase C inhibitors, methods for their preparation, intermediates therefor and pharmaceutical compositions comprising them.
Protein kinase C (PKC) is a family of phospholipid-dependent serine/threonine-specific protein kinases which play an important role in cellular growth control, regulation and differentiation.
Since the activation of PKC has been implicated in several human disease processes, including various forms of cancer, different forms of inflammatory and/or immunological disorders as well as some neurological disorders, inhibition of PKC could be of therapeutic value in treating these conditions.
Several classes of compounds have been identified as PKC inhibitors, e.g. isoquinoline sulphonamides, sphingosine and related sphingolipids, indolocarbazoles and bisindolylmaleimides.
EP 0 328 026 describes the use of certain bisindolylmaleimides, a class of compounds related to the indolocarbazoles, in medicaments for the treatment of various conditions.
Although PKC inhibitors are described in the prior art, there is a need for specific anti-inflammatory and immuno suppressive compounds, which are suitable for oral administration, and for inhalation. Furthermore, there is a need for such compounds, which are more soluble and less colored than the presently known PKC inhibitors.
The present invention provides kinase inhibitors which are particularly PKC inhibitors. methods for their preparation and intermediates used for their preparation.
The kinase inhibitors of the present invention are surprisingly more soluble and less colored than the kinase inhibitors, especially the PKC inhibitors. known in the prior art.
The present invention also provides the use of the compounds of the present invention for the treatment of inflammatory, immunological, bronchopulmonary, cardiovascular, oncological or CNS-degenerative disorders.
Also provided by the present invention are pharmaceutical compositions comprising a compound according to the present invention, as active ingredient, together with a pharmaceutically acceptable adjuvant, diluent or carrier.
The present invention provides a compound of formula (I): 
wherein: one of Ar1 and Ar2 is optionally substituted bicyclic heteroaryl or optionally substituted tricyclic heteroaryl and the other is optionally substituted heteroaryl or optionally substituted aryl; X is O or, when one of Ar1 and Ar2 is optionally substituted bicyclic heteroaryl or optionally substituted tricyclic heteroaryl and the other is optionally substituted heteroaryl then X may also be S; and R is H, OH, NH2 or C1-6 alkyl (itself optionally substituted by amino or hydroxy); or a salt or solvate thereof, or a solvate of a salt thereof; provided that when X is O, R is hydrogen and one of Ar1 and Ar2 is phenyl or phenyl optionally mono-substituted by halogen or C1-4 alkyl then the other is not 3,4-methylenedioxyphenyl, unsubstituted benzthiazol-2-yl, a phthalimide or 1,8-naphthalimide.
Heteroaryl includes monocyclic, bicyclic and tricyclic heteroaryl. Heteroaryl includes pyridinyl, pyridin-2-onyl, thienyl, furyl, pyrrolyl, pyrazolyl, quinolinyl, isoquinolinyl, xanthen-9-yl, quinolizin-3-yl, benzothienyl, benzofuryl, indazolyl, 9H-pyrido[3,4-b]indolyl, 1H-pyrrolo[2,3-b]pyridinyl, 6,7,8,9-tetrahydro-pyrido[1,2-a]indolyl, 2,3-dihydro-1H-pyrrolo[1,2-a]indolyl, indolyl and benzothiophenyl. In one aspect the present invention provides a compound of formula (I) wherein Ar1 and Ar2 are both bicyclic heteroaryl (wherein each heteroaryl has a single heteroatom, such as a N, O or S atom).
It is preferred that aryl is phenyl or naphthyl.
In another aspect Ar1 and Ar2 are selected from pyridinyl, pyridin-2-onyl, thienyl, furyl, pyrrolyl, pyrazolyl, quinolinyl, isoquinolinyl, xanthen-9-yl, quinolizin-3-yl, benzothienyl, benzofuryl, indazolyl, 9H-pyrido[3,4-b]indolyl, 1H-pyrrolo[2,3-b]pyridinyl, 6,7,8,9-tetrahydro-pyrido[1,2-a]indolyl, 2,3-dihydro-1H-pyrrolo[1,2-a]indolyl, indolyl, benzothiophenyl, naphthyl and phenyl.
In a further aspect the present invention provides a compound of formula (I) wherein heteroaryl and bicyclic heteroaryl are, independently, substituted indolyl, such as substituted indol-3-yl, for example substituted at the 1 position.
In another aspect the optional substituents on the heteroaryl (such as mono-, bi- or tri-cyclic heteroaryl) and aryl groups are selected from the group comprising: halo, cyano, nitro, hydroxy, CO2(C1-4 alkyl), C1-8 alkyl (optionally substituted by halo, hydroxy, cyano, C1-4 alkoxy (optionally substituted by NH2, CO2(C1-4 alkyl)), NRaRb, SC(xe2x95x90NH)NH2, C(xe2x95x90NH)NRcRd, Nxe2x95x90C(Re)NRfRg, N(Rh)C(xe2x95x90O)Ri, NHC(xe2x95x90NH)NH2, heterocyclyl (optionally substituted by C1-4 alkyl or phenyl(C1-4)alkyl), phenyl (optionally substituted by C1-4 alkyl (itself optionally substituted by amino), C(xe2x95x90NH)ORj, C(xe2x95x90NH)NRkRl), pyridinyl (optionally substituted by C1-4 alkyl (itself optionally substituted by amino))), C5-6 cycloalkyl (optionally substituted by hydroxy, NRmRn or alkyl (itself optionally substituted by NRoRp)), C5-6 cycloalkenyl (optionally substituted by NRqRr or alkyl (itself optionally substituted by NRsRt)), heterocyclyl (optionally substituted by C1-4 alkyl or C1-4 haloalkyl), phenyl (optionally substituted by halo), C1-6 alkoxy (optionally substituted by phenyl), phenoxy and amino (optionally substituted by C1-4 alkyl); wherein Ra, Rb, Rm, Rn, Ro, Rp, Rq, Rr, Rs and Rt are, independently, hydrogen or C1-4 alkyl (itself optionally substituted by hydroxy, phenyl, CO2H or CO2(C1-4 alkyl)); and, Rc, Rd, Re, Rf, Rg, Rh, Ri, Rj, Rk and Rl are, independently, hydrogen, C1-4 alkyl or phenyl(C1-4)alkyl; or Rk and Rl join to form a heterocyclic ring (such as morpholine).
In a further aspect X is oxygen.
Salts of the compounds of formula (I) are preferably pharmaceutically acceptable salts. pharmaceutically acceptable salts of compounds of the present invention are preferably those well known in the art as being suitable and are, for example, acid addition salts (such as hydrochloride, hydrobromide or acetate salts) or a salt of a compound of formula (I) with an alkyl halide (such as methyl bromide).
Solvates of the compounds or salts of the present invention are conveniently hydrates, such as monohydrates or dihydrates.
Compounds of the present invention include all stereoisomers and mixtures thereof in all proportions.
In a still further aspect the present invention provides a compound of formula (II) or (II): 
wherein: Ar1 and Ar2 are optionally substituted heteroaryl or optionally substituted aryl: R is hydrogen or C1-3 alkyl; X is O or, when Ar1 or Ar2 is optionally substituted heteroaryl X may also be S; R1 and R2 are each independently H, C1-6 alkyl, halogen, C1-3 alkoxy, benzyloxy, hydroxy, cyano, fluoro substituted (C1-3) alkyl, carboxy or carbo(C1-3)alkoxy; R3 is H, C1-6 alkyl, benzyl, C1-3 alkoxy substituted benzyl, hydroxy(C1-6)alkyl, hydroxy(C3-7)cycloalkyl, nitrile(C1-6)alkyl, azido(C1-6)alkyl, amino(C1-6)alkyl, amino(C3-7)cycloalkyl, aminomethyl(C3-7)cycloalkyl, amino(C5-7)cycloalkenyl, (mono- or di- C1-6alkyl) amino(C1-6)alkyl, benzylamino(C1-6)alkyl, (mono- or di-C1-6alkyl) amino(C3-7)cycloalkyl, (mono- or di-C1-6alkyl) aminomethyl(C3-7)cycloalkyl, (amino(C3-7)alkylphenyl)(C1-3)alkyl, amino(C1-3)alkylphenyl, guanidino(C1-6)alkyl, amidino(C1-6)alkyl, amidinothio(C1-6)alkyl, [N,N-di-(C1-6)alkyl]amidino(C1-6)alkyl, amidino(C1-3)alkylphenyl, [N,N-mono- or di-(C1-6)alkyl]amidino(C1-3)alkylphenyl, (N-benzyl)amidino(C1-3)alkylphenyl, (4-morpholinyl)imino(C1-3)alkylphenyl, benzimic acid methyl ester(C1-3)alkyl, hydroxy(C1-3)alkylamino (C1-6)alkyl, carboxy(C1-3)alkylamino (C1-6)alkyl, carboxymethyl(C1-3)alkylamino (C1-6)alkyl, amino(C1-3)alkyloxy (C2-6)alkyl, formamide(C1-6)alkyl, (N,N-dimethyl)imidoformamide(C1-6)alkyl, or a group of the formula
xe2x80x94(CH2)n-Het
in which n is an integer of 0-6, and Het is an optionally substituted 5- or 6-membered heterocyclic group; R4 is H, C1-3 alkyl or together with R3, forms an annulated ring which may be substituted by hydroxy(C1-3) alkyl or amino(C1-3) alkyl; or a salt or a solvate thereof, or a solvate of such a salt. preferred are compounds of formula (II) and (III) in which Ar1 or Ar2 is optionally substituted bicyclic heteroaryl.
In another aspect the present invention provides a compound of formula (XV): 
wherein R, R1, R2, R3 and R4 are as defined above and Ar2 is optionally substituted bicyclic heteroaryl or optionally substituted tricyclic heteroaryl.
In yet another aspect the present invention provides a compound of formula (IV): 
wherein R1-R4 are as defined in formula (II) and (III); R5 is H, C1-6 alkyl, benzyl, hydroxy(C1-6)alkyl or amino(C1-6)alkyl; R6 and R7 are each independently H, C1-3 alkyl, halogen, fluorosubstituted C1-3 alkyl, C1-3 alkoxy, benzyloxy, hydroxy, cyano, carboxy or carbo(C1-3)alkoxy; or a salt or solvate thereof, or a solvate of such a salt.
For compounds of formula (IV), the following independent preferences apply: R3 or R5 is aminopropyl, aminobutyl, aminopentyl, aminocyclopentyl, aminomethylcyclopentyl, (dimethylamino)methylcyclopentyl guanidinopropyl, amidinopropyl, amidinobutyl, amidinothiopropyl, ethylaminopropyl, dimethylaminopropyl, dimethylaminobutyl, morpholinopropyl, methylpiperazinopropyl, methylpiperidinyl, piperidinomethyl, benzylpiperidinomethyl, diethylaminocyclopentyl or dimethylaminocyclopentyl;
R1, R2, R6 and R7 are each independently methyl, methoxy, cyano or halogen, preferably F or Cl.
In yet another aspect he present invention provides compounds of formula (I): 
wherein:
Ar1 and Ar2 are
i) the same or different bicyclic heteroaromatic group(s), or
ii) independently bicyclic heteroaromatic group, and an optionally substituted aromatic or heteroaromatic group,
X is O or S, and
R is H, OH, NH2, C1-6alkyl, aminoC1-6alkyl or hydroxyC1-6alkyl,
and salts and solvates thereof and solvates of such salts.
In preferred embodiments of formula (I), when Ar1 and/or Ar2 are a bicyclic heteroaromatic or heteroaromatic group they include a single heteroatom selected from N, O and S.
In yet more preferred embodiments of formula (I), Ar1 and/or Ar2 are selected from benzothiophene, naphthyl, optionally substituted phenyl and optionally substituted indolyl. Optional substituents for Ar1 and/or Ar2 include aminopropyl, aminobutyl, ethylaminopropyl propyl, ethylaminobutyl, dimethylaminopropyl, dimethylaminobutyl, aminocyclopentyl, ethylaminocyclopentyl, dimethylaminocyclopentyl, amidinoalkyl, amidinothioalkyl and guanidinoalkyl.
Preferred embodiments of formula (I) are compounds of formula (II) and (III) 
wherein:
Ar is an optionally substituted aromatic, heteroaromatic or bicyclic heteroaromatic group
R is hydrogen or C1-3 alkyl
R1 and R2 are each independently H, C1-6 alkyl, halogen, C1-3 alkoxy, bensyloxy, hydroxy, carboxy, carboC1-3alkoxy, carbamoyl and C1-3 alkylcarbamoyl.
R3 is H, C1-6alkyl, bensyl, C1-3alkoxy substituted bensyl, hydroxyC1-6alkyl, hydroxiC3-7cykloalkyl, nitrileC1-6alkyl, azidoC1-6alkyl, aminoC1-6alkyl, aminoC3-7cycloalkyl, (mono- or di-C1-6alkyl) aminoC1-6alkyl, (mono- or di-C1-6alkyl) aminoC3-7cycloalkyl, (aminoC1-3alkylphenyl)C1-3alkyl, aminoC1-3alkylphenyl, guanidinoC1-6alkyl, amidinoC1-6alkyl, amidinothioC1-6alkyl, aminoC1-6 alkoxy substituted alkyl, aminoC1-6 hydroxy substituted alkyl, aminoC1-6 amino substituted alkyl or a group of the formula
xe2x80x94(CH2)n-Het
in which
n is an integer of 1-6, and
Het is an optionally substituted 5- or 6-membered heterocyclic group
R4 is H, C1-3 alkyl or together with R3, forms an annulated ring which may be substituted by hydroxyC1-3 alkyl or aminoC1-3 alkyl,
and salts and solvates thereof and solvates of such salts.
More preferred embodiments of formula (I) are compounds of formula (II) and (III), in which Ar is an optionally substituted bicyclic heteroaromatic group.
Even more preferred embodiments of formula (I) are compounds of formula (IV) 
wherein
R1-R4 are as defined in formula (II) and (III),
R5 is H, C1-6 alkyl, bensyl, hydroxyC1-6 alkyl, aminoC1-6 alkyl,
R6 and R7 are each independently H, C1-3 alkyl, halogen, C1-3 alkoxy, bensyloxy, hydroxy, carboxy, carboC1-3alkoxy, carbamoyl and C1-3 alkylcarbamoyl,
and salts and solvates thereof and solvates of such salts.
For compounds of formula (IV), the following independent preferences apply:
xe2x80x94R3 or R5 is aminoethyl, aminopropyl, aminobutyl, aminomethyl benzyl, aminocyclopentyl guanidinopropyl, amidinobutyl, amidinothiopropyl, ethylaminopropyl, ethylaminobutyl, dimethylaminopropyl, dimethylaminobutyl, ethylaminocyclopentyl, or dimethylaminocyclopentyl.
xe2x80x94R1, R2, R6 and R7 are each independently halogen, preferably F or Cl.
Preferred compounds according to the present invention include:
4-[1-(3-Aminopropyl)-5-fluoro-indol-3-yl]-5-(5-fluoro-1-methyl-indol-3-yl)-2,4dihydro-[1,2,4]triazol-3-one
4-[1-(4-Aminobutyl)-5-fluoro-indol-3-yl]-5-(5-fluoro-1-methyl-indol-3-yl)-2,4dihyro-[1,2,4]triazol-3-one
4-[1-(5-Aminopentyl)-5-fluoro-indol-3-yl]-5-(5-fluoro-1-methyl-indol-3-yl)-2,4-dihydro-[1,2,4]triazol-3-one
4-[1-(3-Dimethylamino-propyl)-5-fluoro-indol-3-yl]-5-(5-fluoro-1-methyl-indol-3-yl-2,4-dihydro-[1,2,4]triazol-3-one
4-[1-(3-Dimethylamino-butyl)-5-fluoro-indol-3-yl]-5-(5-fluoro-1-methyl-indol-3-yl)-2,4-dihydro-[1,2,4]triazol-3-one
4-[1-(3-Ethylamino-propyl)-5-fluoro-indol-3-yl]-5-(5-fluoro-1-methyl-indol-3-yl)-2,4-dihydro-[1,2,4]triazol-3-one
4-[1-(3-Aminopropyl)-5-fluoro-indol-3-yl]-5-(1-methyl-indol-3-yl)-2,4-dihydro-[1,2,4]triazol-3-one
4-[1-(3-Aminopropyl)-5-fluoro-indol-3-yl]-5-(1H-indol-3-yl)-2,4-dihydro-[1,2,4]triazol-3-one
5-(5-Fluoro-1-methyl-indol-3-yl)-4-[5-fluoro-1-(3-morpholin-4-yl-propyl)-indol-3-yl]-2,4-dihydro-[1,2,4]triazol-3-one
5-(5-Fluoro-1-methyl-indol-3-yl)-4-{5-fluoro-1-[3-(4-methyl-piperazin-1-yl)-propyl]indol-3-yl }-2,4-dihydro-[1,2,4]triazol-3-one
2-(3-{5-Fluoro-3-[3-(5-fluoro-1-methyl-indol-3-yl)-5-oxo-1,5-dihydro-[1,2,4]triazol-4-yl]-indol-1-yl}-propyl)-isothiourea
N-(3-{5-Fluoro-3-[3-(5-fluoro-1-methyl-indol-3-yl)-5-oxo-1,5-dihydro-[1,2,4]triazol-4-yl-indol-1-yl}-propyl]-guanidine
5-{5-Fluoro-3-[3-(5-fluoro-1-methyl-indol-3-yl)-5-oxo-1,5-dihydro-[1,2,4]triazol-4-yl]indol-1-yl}-butanamidine
5-{5-Fluoro-3-[3-(5-fluoro-1-methyl-indol-3-yl)-5-oxo-1,5-dihydro-[1,2,4]triazol-4-yl]indol-1-yl}-pentanamidine
4-[1(S)-(3(S)-Aminocyclopentyl)-5-fluoro-indol-3-yl]-5-(5-fluoro-1-methyl-indol-3-yl)-2,4-dihydro-[1,2,4]triazol-3-one
4-[1(R)-(3(R)-Aminocyclopentyl)-5-fluoro-indol-3-yl]-5-(5-fluoro-1-methyl-indol-3-yl)-2,4-dihydro-[1,2,4]triazol-3-one
4-[1(S)-(3(R)-Aminocyclopentyl)-5-fluoro-indol-3-yl]-5-(5-fluoro-1-methyl-indol-3yl)-2,4-dihydro-[1,2,4]triazol-3-one
4-[1(R)-(3(S)-Aminocyclopentyl)-5-fluoro-indol-3-yl]-5-(5-fluoro-1-methyl-indol-3-yl)-2,4-dihydro-[1,2,4]triazol-3-one
4-[1(S)-(3(S)-Aminocyclopentyl)-indol-3-yl]-5-(1-methyl-indol-3-yl)-2,4-dihydro-[1,2,4]triazol-3-one
4-[1(S)-(3(S)-Dimethylamino-cyclopentyl)-5-fluoro-indol-3-yl]-5-(5-fluoro-1-methyl-indol-3-yl)-2,4-dihydro-[1,2,4]triazol-3-one
4-[1(S)-(3(S)-Diethylamino-cyclopentyl)-5-fluoro-indol-3-yl]-5-(5-fluoro-1-methyl-indol-3-yl)-2,4-dihydro-[1,2,4]triazol-3-one
4-[1(S)-(3(R)-Aminomethyl-cyclopentyl)-5-fluoro-indol-3-yl]-5-(5-fluoro-1-methyl-indol-3-yl)-2,4-dihydro-[1,2,4]triazol-3-one
4-[1(S)-(3(R)-Dimethylaminomethyl-cyclopentyl)-5-fluoro-indol-3-yl]-5-(5-fluoro-1-methyl-indol-3-yl)-2,4-dihydro-[1,2,4]triazol-3-one
5-(5-Fluoro-1-methyl-indol-3-yl)-4-(5-fluoro-1-piperidin-4-ylmethyl-indol-3-yl)-2,4-dihydro-[1,2,4]triazol-3-one
5-(5-Fluoro-1-methyl-indol-3-yl)-4-[5-fluoro-1-(1-methyl-piperidin-4-yl)-indol-3-yl)-2,4dihydro-[1,2,4]triazol-3-one
4-[1-(1-Benzyl-piperidin-4-ylmethyl)-5-fluoro-indol-3-yl]-5(5-fluoro-1-methyl-indol-3yl)-2,4-dihydro-[1,2,4]triazol-3-one
4-[1-(3-Aminopropyl)-5-fluoro-indol-3-yl]-5-(1,5-dimethyl-indol-3-yl)-2,4-dihydro-[1,2,4]triazol-3-one
4-[1-(3-Aminopropyl)-5-fluoro-indol-3-yl]-5-(5-chloro-1-methyl-indol-3-yl)-2,4-dihydro-[1,2,4]triazol-3-one
4-[1-(3-Aminopropyl)-5-fluoro-indol-3-yl]-5-(5-cyano-1-methyl-indol-3-yl)-2,4-dihydro-[1,2,4]triazol-3-one
4-[1-(3-Aminopropyl)-5-fluoro-indol-3-yl]-5-(5-methoxy-1-methyl-indol-3-yl)-2,4-dihydro-[1,2,4]triazol-3-one
4-[1-(3-Aminopropyl)-5-chloro-indol-3-yl]-5-(5-chloro-1-methyl-indol-3-yl)-2,4-dihydro-[1,2,4]triazol-3-one
4-(1-Methyl-indol-3-yl)-5-(8-aminomethyl-6,7,8,9-tetrahydro-pyrido[1,2-a]indol-10-yl)-2,4-dihydro-[1,2,4]triazol-3-one
or a salt or solvate thereof or a solvate of such a salt.
Preparation of the Compounds of the Invention
Compounds of formula (I) may be synthesized in the following ways:
(a) Compounds of formula (I), in which R is C1-3 alkyl (optionally substituted by amino or hydroxy), comprising alkylating a compound of formula (I) in which R is hydrogen with the corresponding C1-3 alkyl (optionally substituted by amino or hydroxy) alkylating agent.
(b) Compounds of formula (I), in which R is H may be synthesized by intramolecular condensation of a compound of formula (VI): 
in which Ar1 and Ar2 are as defined for formula (I).
(c) Compounds of formula (I) may be synthesized by converting a compound of formula (I) to a salt, especially a pharmaceutically acceptable salt thereof, or vice versa; or converting a salt, especially a pharmaceutically acceptable salt of a compound of formula (I) into a different salt, especially a pharmaceutically acceptable salt.
The condensation may be conveniently performed in the presence of trimethylsilyl triflate or bistrimethylsilyl acetamide, and a base e.g. triethylamine in dimethyl formamide at a temperature in the range of from about 100xc2x0 C. to about 160xc2x0 C., suitably from 115xc2x0 C. to 145xc2x0 C. and preferably at about 130xc2x0 C., for a period of time in the range of from about 5 min to about 6 h, suitably from 15 min to 3 h, preferably for about 1h.
A compound of formula (I) wherein Ar1, Ar2 and/or R carries one or more functional groups which might be sensitive to, or interfere with, the reaction conditions in the processes in (a) or (b), can be prepared by using a corresponding starting material in which the functional group(s) is suitably protected and then deprotected at the end of the process of (a) or (b).
Functional groups that might be sensitive to or interfere with the reaction conditions in processes (a) or (b), as well as suitable protecting groups and deprotecting methods, are evident to those skilled in the art.
The starting materials for the above processes (a), (b) and (c) may be made by the methods described herein and particularly by those methods set out in the Examples or by methods analogous thereto. Other conventional methods for making the starting materials will be evident to those skilled in the art.
A compound of formula (II) or (III), or a salt thereof, in which at least one of R3 or Ar carries an amino or hydroxy group can be prepared by deprotecting the corresponding compound of formula (II) and (III) wherein said amino or hydroxy group is protected.
In the processes described above, the protecting groups and conditions for deprotection are well known to those skilled in the art. Suitable protecting groups for amino groups are e.g t-butoxy carbonyl groups and the deprotecting agent may be trifluoroacetic acid in a suitable solvent e.g. a mixture of acetonitrile and water. The hydroxy groups may be protected as their corresponding tert-butyldimethylsilyl (TBDMS) oxy groups and the deprotecting agent may be acetic acid in e.g. water. The deprotecting step may be carried out in a suitable solvent, e.g. tetrahydrofuran at about 60-80xc2x0 C., e.g. for about 2 hours.
The use of protecting groups is fully described in xe2x80x9cProtective Groups in Organic Chemistryxe2x80x9d, edited by J. W. F. McOmie, Plenum Press (1973) and xe2x80x9cProtective Groups in Organic Synthesisxe2x80x9d, 2nd edition, T. W. Greene and P. G. M. Wutz, Wiley-Interscience (1991).
Compounds of formula (II) or (III), in which R3 is an alkyl carrying an amino group, may be prepared by reduction of a compound of formula (IX) or (X) respectively: 
wherein R, R1, R2, R4 and Ar are as defined for formula (II) and (III), and R311 is an alkyl group.
In the process above, the conditions for the reduction are well known to those skilled in the art. Suitable conditions for the reduction of the azido group are e.g. hydrogenation on Pd/C at atmospheric pressure or the use of Staudinger conditions i.e. triphenyl phosphine in pyridine, followed by addition of ammonia (aq).
Compounds of formula (II) or (III), in which R3 is an alkyl carrying a thioamidino, monoalkyl amino, dialkyl amino, or a trialkyl amino group may be prepared by reaction of a compound of formula (XI) or (XII), respectively, with thiourea, or a suitable monoalkyl-, diakyl- or trialkyl amine: 
wherein R, R1, R2, R4 and Ar are as defined in formula (II) and (III), R311 is an alkyl group and LG is a leaving group, e.g. mesylate or bromide.
Compounds of formula (XI) and (XII) may be synthesized by transforming under standard conditions well known to the person skilled in the art the alcohol function in compounds of formula (XIII) and (XIV): 
wherein R, R1, R2, R4 and Ar are as defined in formula (II) and (III) and R311 is an alkyl group.
Compounds of formula (II) in which R3 is alkyl or phenylalkyl carrying an amidino or a guanidino group may be synthesized using standard methods, from compounds of formula (XV) corresponding to formula (II), but in which R3 is alkyl carrying a nitrile or primary amine, by reacting with hydrogen chloride in ethanol followed by ammonia in methanol or by reacting with 3,5-dimethylpyrazole-1-carboxamidinium nitrate in refluxing ethanol and in the presence of a base, respectively.
Compounds of formula (II) or (III), as defined above, wherein R3 is alkyl carrying an amidino or guanidino group can be prepared by: (i) reacting a compound of formula (II) or (III), in which R3 is alkyl carrying a nitrile, with hydrogen chloride in ethanol followed by ammonia in methanol; or, (ii) reacting a compound of formula (II) or (III), in which R3 is alkyl carrying a primary amine, with 3,5-dimethylpyrazole-1-carboxamidinium nitrate in refluxing ethanol in the presence of a base.
Compounds of formula (II) or (III), as defined above, wherein R3 is alkyl or phenylalkyl carrying a N-substituted or N,N-di-substituted amidino group, can be prepared by reacting a compound of formula (II) or (III), in which R3 is alkyl or phenyl alkyl carrying a nitrile, with hydrogen chloride in methanol, followed by treatment with the appropriate amine in methanol.
Persons skilled in the art will appreciate that, in order to obtain compounds of the invention in an alternative, and, on some occasions, more convenient, manner, the individual process steps mentioned herein may be performed in a different order, and/or the individual reactions may be performed at a different stage in the overall route. This will e.g. on factors such as the nature of other functional groups present in a particular substrate, the availability of key intermediates and the protecting group strategy (if any) to be adopted.
Novel intermediates as described hereinbefore and their use in the manufacture of other compounds of the present invention also form part of the invention. Thus, according to a further aspect of the invention there is provided an intermediate compound of formula (VI), (IX), (X), (XI), (XII), (XIII) or (XIV) as defined hereinbefore, or a protected derivative of any of these compounds.
Prodrugs
It will also be appreciated by those skilled in the art that, although certain protected derivatives of compounds of formula (I), (II), (III), (IV) and (XV), which may be made prior to a final deprotection stage, may not possess pharmacological activity as such, they may be administered parenterally or orally and thereafter metabolized in the body to form compounds of the invention which are pharmacologically active. Such derivatives may therefore be described as xe2x80x9cprodrugsxe2x80x9d. Moreover, certain compounds of formula (I), (II), (III), (IV) and (XV) may act as prodrugs of other compounds of formula (I), (II), (III), (IV) and (XV).
All prodrugs of compounds of formula (I), (II), (III), (IV) and (XV) are included within the scope of the present invention.
Medical and Pharmaceutical Use
Also provided according to the present invention are compounds of the present invention for use in medical therapy; the use of compounds of the present invention in the manufacture of medicaments for use in the treatment of the conditions described herein: and methods of medical therapy comprising the administration of a therapeutically effective amount of a compound of the present invention to an individual requiring such therapy.
The term xe2x80x98medical therapyxe2x80x99 as used herein is intended to include prophylactic, diagnostic and therapeutic regimens carried out in vivo or ex vivo on humans or other mammals.
The compounds of formula (I), (II), (III), (IV) and (XV) and pharmaceutically acceptable salts thereof, are useful because they demonstrate pharmacological activity. In particular they demonstrate activity as kinase inhibitors, especially PKC inhibitors, e.g. as is shown by their activity in the in vitro assays described in Jirousek, M. J. et al, J. Med. Chem. 1996, 39, 2664-2671; or as described in Granet, R. A. et al, Analyt. Biochem. 1987; 163, 458-463; Olsson, H. et al, Cell Signal 1989, 1, 405-410; and Chakravarthy, B. R. et al, Analyt. Biochem. 1991, 196, 144-150.
The compounds of the invention are indicated for use in the treatment of inflammatory, immunological. bronchopulmonary, cardiovascular, oncological or CNS-degenerative disorders; preferably for oral or topical treatment of inflammatory and/or immunological disorders, such as the oral or topical treatment of airway diseases involving inflammatory conditions, e.g. asthma, chronic obstructive pulmonary disease (COPD), including chronic bronchitis and emphysema; or atopic diseases, e.g. rhinitis or atopic dermatitis; inflammatory bowel diseases, e.g. Crohn""s disease or colitis; autoimmune diseases e.g. multiple sclerosis, diabetes, atherosclerosis, psoriasis, systemic lupus erythematosus or rheumatoid arthritis; malignant diseases, e.g. skin or lung cancer; HIV infections or AIDS; or for inhibiting rejection of organs/transplants. The compounds of the invention are also indicated for use in treatment of heart failure, and in treatment of diabetic patients with macular edema or diabetic retinopathy.
Thus, in a further aspect the present invention provides the use of a compound of formula (I): 
wherein: one of Ar1 and Ar2 is optionally substituted bicyclic heteroaryl or optionally substituted tricyclic heteroaryl and the other is optionally substituted heteroaryl or optionally substituted aryl; X is O or S; and R is H, OH, NH2 or C1-6 alkyl (itself optionally substituted by amino or hydroxy); or a salt, solvate or hydrate thereof, or a solvate or a hydrate of a salt thereof: in the manufacture of a medicament for use in the treatment of inflammatory, immunological, bronchopulmonary, cardiovascular, oncological or CNS disorders.
A method of treating a PKC mediated disease state in mammals which comprises administering to a mammal in need of such treatment an effective amount of a compound of formula (I) as defined in the preceding paragraph or a salt, solvate or hydrate thereof, or a solvate or a hydrate of a salt thereof.
Pharmaceutical Preparations
The dose of the compound to be administered will depend on the relevant indication, the age, weight and sex of the patient and may be determined by a physician. The dosage will preferably be in the range of from 0.01 mg/kg to 10 mg/kg.
The compounds may be administered topically, e.g. to the lung and/or the airways, in the form of solutions, suspensions, HFA aerosols or dry powder formulations, e.g. formulations in the inhaler device known as the Turbuhaler(copyright); or systemically, e.g. by oral administration in the form of tablets, pills, capsules, syrups, powders or granules, or by parenteral administration, e.g. in the form of sterile parenteral solutions or suspensions, or by rectal administration, e.g. in the form of suppositories.
The compounds of the invention may be administered on their own or as a pharmaceutical composition comprising the compound of the invention in combination with a pharmaceutically acceptable diluent, adjuvant and/or carrier. Particularly preferred are compositions not containing material capable of causing an adverse, e.g. an allergic, reaction.
Dry powder formulations and pressurized HFA aerosols of the compounds of the invention may be administered by oral or nasal inhalation. For inhalation the compound is desirably finely divided. The finely divided compound preferably has a mass median diameter of less than 10 xcexcm, and may be suspended in a propellant mixture with the assistance of a dispersant, such as a C8-C20 fatty acid or salt thereof, (e.g. oleic acid), a bile salt. a phospholipid, an alkyl saccharide, a perfluorinated or polyethoxylated surfactant, or other pharmaceutically acceptable dispersant.
The compounds of the invention may also be administered by means of a dry powder inhaler. The inhaler may be a single or a multi dose inhaler, and may be a breath actuated dry powder inhaler.
One possibility is to mix the finely divided compound with a carrier substance, e.g. a mono-, di- or polysaccharide, a sugar alcohol, or another polyol. Suitable carriers are sugars, e.g. lactose, glucose, raffinose, melezitose, lactitol, maltitol, trehalose, sucrose, mannitol; and starch. Alternatively the finely divided compound may be coated by another substance. The powder mixture may also be dispensed into hard gelatin capsules, each containing the desired dose of the active compound.
Another possibility is to process the finely divided powder into spheres which break up during the inhalation procedure. This spheronized powder may be filled into the drug reservoir of a multidose inhaler, e.g. that known as the Turbuhaler(copyright) in which a dosing unit meters the desired dose which is then inhaled by the patient. With this system the active compound, with or without a carrier substance, is delivered to the patient.
For oral administration the active compound may be admixed with an adjuvant or a carrier, e.g. lactose, saccharose, sorbitol, mannitol; a starch, e.g. potato starch, corn starch or amylopectin; a cellulose derivative; a binder, e.g. gelatin or polyvinylpyrrolidone, and/or a lubricant, e.g. magnesium stearate, calcium stearate, polyethylene glycol, a wax, paraffin. and the like, and then compressed into tablets. If coated tablets are required, the cores, prepared as described above, may be coated with a concentrated sugar solution which may contain e.g. gum arabic, gelatin, talcum, titanium dioxide, and the like. Alternatively, the tablet may be coated with a suitable polymer dissolved in a readily volatile organic solvent.
For the preparation of soft gelatin capsules, the compound may be admixed with e.g. a vegetable oil or polyethylene glycol. Hard gelatin capsules may contain granules of the compound using either the above mentioned excipients for tablets. Also liquid or semisolid formulations of the drug may be filled into hard gelatin capsules.
Liquid preparations for oral application may be in the form of syrups or suspensions, for example solutions containing the compound, the balance being sugar and a mixture of ethanol, water, glycerol and propylene glycol. Optionally such liquid preparations may contain coloring agents. flavoring agents, saccharine and/or carboxymethylcellulose as a thickening agent or other excipients known to those skilled in art.
The compounds of the invention may also be administered in conjunction with other compounds used for the treatment of the above conditions.
The following Examples are intended to illustrate, but in no way limit the scope of the invention.
All reactions were performed in dried glassware in an argon or nitrogen atmosphere at room temperature, unless otherwise noted. Tetrahydrofuran (THF) was distilled from sodium benzophenone ketyl under N2 prior to use. N,N-Dimethyl formamide (DMF) was distilled from calcium hydride and stored over molecular sieves. All other solvents and reagents were used as received.
1H-NMR spectra were recorded on a Varian Inova-400 or Unity-500+ instrument. The central solvent peak of chloroform-d (xcex4H 7.27 ppm), dimethylsulfoxide-d6 (xcex4H 2.50 ppm) or methanol-d4 (xcex4H 3.35 ppm) were used as internal references. Low-resolution mass spectra were recorded on an Autospec-Q, Fisons Analytical, double focusing sector instrument equipped with a LSIMS interface. Low resolution mass spectra were also obtained on a Hewlett Packard 1 100 LC-MS system equipped with an APCI ionization chamber.
Analytical HPLC was run on a Hewlett Packard LC-MS 1100, using a C-18 reversed phase column and eluting with the following general system: acetonitrile:water (20:80 to 90:10 gradient) containing 0.1% TFA. Preparative LC was run on a Kromasil KR-100-10-C18 column (250xc3x9750 mm), using different proportions of acetonitrile:water as eluent, containing 0.1% TFA.
Reversed-phased column chromatography was done with pre-packed columns (Merck, Lobar, LiChroprep RP-18 equipped with a peristaltic pump) using methanol:water and 0.1% acid (TFA, HCl. or HBr) as eluent.
Flash chromatography was performed on silica (Merck 40-63 xcexcm) with the eluents indicated in the specific Examples.
IR was run on a Perkin Elmer 16 PC FT-IR.